Top

Published in:

Open Access 12-05-2023 | Rheumatoid Arthritis | Original Research

Association of Hydroxychloroquine Use with a Dose-Dependent Decrease in Mortality Risk in Patients with Elderly-Onset Rheumatoid Arthritis

Authors: Ching-Tsai Lin, Wen-Nan Huang, Jun-Peng Chen, Wei-Ting Hung, Tsu-Yi Hsieh, Hsin-Hua Chen, Kuo-Tung Tang, Der-Yuan Chen, Yi-Hsing Chen, Yi-Ming Chen

Published in: Rheumatology and Therapy | Issue 4/2023

Abstract

Introduction

Elderly-onset rheumatoid arthritis (EORA) is associated with an increased mortality risk; however, the effect of conventional synthetic, biologics or targeted synthetic disease-modifying anti-rheumatic drugs (csDMARDs, bDMARDs or tsDMARDs) on the EORA-specific mortality risk is unknown. In this study, we investigated the risk factors for all-cause mortality of patients with EORA.

Methods

Data of EORA patients diagnosed with RA at age > 60 years between January 2007 and June 2021 were extracted from the electronic health record of Taichung Veterans General Hospital, Taiwan. Multivariable Cox regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). The survival of patients with EORA was analyzed by Kaplan-Meier method.

Results

Among the 980 EORA patients who were enrolled (survivors 852 and non-survivor 128), the significant mortality-associated risk factors [HR (95% CI)] included higher age (1.10 [1.07–1.12], p < 0.001), male sex (1.92 [1.22–3.00], p = 0.004), current smoker (2.31 [1.10–4.87], p = 0.027) and underlying malignancy (1.89 [1.20–2.97], p = 0.006). Hydroxychloroquine treatment conferred protection against mortality in patients with EORA (HR 0.30, 95% CI 0.14–0.64, p = 0.002). Patients with malignancy who did not receive hydroxychloroquine treatment had the highest mortality risk compared with their counterparts. Patients with a monthly cumulative dose of hydroxychloroquine dose < 1374.5 mg had the lowest survival rate compared to patients who received hydroxychloroquine 1374.5–5778.5 and ≥ 5778.5 mg.

Conclusion

Hydroxychloroquine treatment is associated with survival benefits in patients with EORA, and prospective studies are needed to validate the abovementioned findings.

Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73(1):62–8. https://doi.org/10.1136/annrheumdis-2013-204223.CrossRefPubMed

Hitchon CA, Boire G, Haraoui B, et al. Self-reported comorbidity is common in early inflammatory arthritis and associated with poorer function and worse arthritis disease outcomes: results from the Canadian Early Arthritis Cohort. Rheumatology (Oxford). 2016;55(10):1751–62. https://doi.org/10.1093/rheumatology/kew061.CrossRefPubMed

Callahan LF, Pincus T, Huston JW, Brooks RH, Nance EP, Kaye JJ. Measures of activity and damage in rheumatoid arthritis: depiction of changes and prediction of mortality over five years. Arthritis Care Res. 1997;10(6):381–94. https://doi.org/10.1002/art.1790100606.CrossRefPubMed

van Schaardenburg D, Breedveld FC. Elderly-onset rheumatoid arthritis. Semin Arthritis Rheum. 1994;23(6):367–78. https://doi.org/10.1016/0049-0172(94)90087-6.CrossRefPubMed

Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822–32. https://doi.org/10.1038/s41591-019-0675-0.CrossRefPubMedPubMedCentral

Serhal L, Lwin MN, Holroyd C, Edwards CJ. Rheumatoid arthritis in the elderly: characteristics and treatment considerations. Autoimmun Rev. 2020;19(6):102528. https://doi.org/10.1016/j.autrev.2020.102528.CrossRefPubMed

van der Heijde DM, van Riel PL, van’t Leeuwen MA, van Hof MA, van Rijswijk MH, van de Putte LB. Older versus younger onset rheumatoid arthritis: results at onset and after 2 years of a prospective followup study of early rheumatoid arthritis. J Rheumatol. 1991;18(9):1285–9.PubMed

Targońska-Stępniak B, Grzechnik K, Kolarz K, Gągoł D, Majdan M. Systemic Inflammatory parameters in patients with elderly-onset rheumatoid arthritis (EORA) and young-onset rheumatoid arthritis (YORA)-an observational study. J Clin Med. 2021;10(6):1204–15. https://doi.org/10.3390/jcm10061204.CrossRefPubMedPubMedCentral

Widdifield J, Bernatsky S, Paterson JM, et al. Trends in excess mortality among patients with rheumatoid arthritis in Ontario, Canada. Arthritis Care Res (Hoboken). 2015;67(8):1047–53. https://doi.org/10.1002/acr.22553.CrossRefPubMed

10.

Zhang Y, Lu N, Peloquin C, et al. Improved survival in rheumatoid arthritis: a general population-based cohort study. Ann Rheum Dis. 2017;76(2):408–13. https://doi.org/10.1136/annrheumdis-2015-209058.CrossRefPubMed

11.

Wolfe F, Mitchell DM, Sibley JT, et al. The mortality of rheumatoid arthritis. Arthritis Rheum. 1994;37(4):481–94. https://doi.org/10.1002/art.1780370408.CrossRefPubMed

12.

Sharma TS, Wasko MC, Tang X, et al. Hydroxychloroquine use is associated with decreased incident cardiovascular events in rheumatoid arthritis patients. J Am Heart Assoc. 2016;5(1):1–6. https://doi.org/10.1161/jaha.115.002867.CrossRef

13.

Wasko MC, Hubert HB, Lingala VB, et al. Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis. JAMA. 2007;298(2):187–93. https://doi.org/10.1001/jama.298.2.187.CrossRefPubMed

14.

Rempenault C, Combe B, Barnetche T, et al. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2018;77(1):98–103. https://doi.org/10.1136/annrheumdis-2017-211836.CrossRefPubMed

15.

Sugihara T, Ishizaki T, Onoguchi W, et al. Effectiveness and safety of treat-to-target strategy in elderly-onset rheumatoid arthritis: a 3-year prospective observational study. Rheumatology (Oxford). 2021;60(9):4252–61. https://doi.org/10.1093/rheumatology/keaa922.CrossRefPubMed

16.

Balanescu AR, Citera G, Pascual-Ramos V, et al. Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL surveillance trial. Ann Rheum Dis. 2022;81(11):1491–503. https://doi.org/10.1136/ard-2022-222405.CrossRefPubMed

17.

Deal CL, Meenan RF, Goldenberg DL, et al. The clinical features of elderly-onset rheumatoid arthritis. A comparison with younger-onset disease of similar duration. Arthritis Rheum. 1985;28(9):987–94. https://doi.org/10.1002/art.1780280905.CrossRefPubMed

18.

Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24. https://doi.org/10.1002/art.1780310302.CrossRefPubMed

19.

Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81. https://doi.org/10.1002/art.27584.CrossRefPubMed

20.

Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–8. https://doi.org/10.1002/art.1780380107.CrossRefPubMed

21.

Chen YH, Chien RN, Huang YH, et al. Screening and management of hepatitis B infection in rheumatic patients scheduled for biologic therapy: consensus recommendations from the Taiwan Rheumatology Association. Formos J Rheumatol. 2012;26:1–7.

22.

Chen YH, Su WJ, Hsieh SJ, et al. 2015 TRA revised recommendations for screening and management of tuberculosis infection in patients before and after anti-tumor necrosis factor -alpha biological treatment. Form J Rheumatol. 2015;29:1–8.

23.

Glennås A, Kvien TK, Andrup O, Karstensen B, Munthe E. Recent onset arthritis in the elderly: a 5 year longitudinal observational study. J Rheumatol. 2000;27(1):101–8.PubMed

24.

Solomon DH, Avorn J, Katz JN, et al. Immunosuppressive medications and hospitalization for cardiovascular events in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(12):3790–8. https://doi.org/10.1002/art.22255.CrossRefPubMed

25.

Ke Y, Dai X, Xu D, et al. Features and outcomes of elderly rheumatoid arthritis: does the age of onset matter? A comparative study from a single center in China. Rheumatol Ther. 2021;8(1):243–54. https://doi.org/10.1007/s40744-020-00267-8.CrossRefPubMed

26.

Sugihara T. Treatment strategies for elderly-onset rheumatoid arthritis in the new era. Mod Rheumatol. 2022;32(3):493–9. https://doi.org/10.1093/mr/roab087.CrossRefPubMed

27.

Nirk EL, Reggiori F, Mauthe M. Hydroxychloroquine in rheumatic autoimmune disorders and beyond. EMBO Mol Med. 2020;12(8):e12476. https://doi.org/10.15252/emmm.202012476.CrossRefPubMedPubMedCentral

28.

Sorour AA, Kurmann RD, Shahin YE, et al. Use of hydroxychloroquine and risk of heart failure in patients with rheumatoid arthritis. J Rheumatol. 2021;48(10):1508–11. https://doi.org/10.3899/jrheum.201180.CrossRefPubMedPubMedCentral

29.

Wu CL, Chang CC, Kor CT, et al. hydroxychloroquine use and risk of CKD in patients with rheumatoid arthritis. Clin J Am Soc Nephrol. 2018;13(5):702–9. https://doi.org/10.2215/cjn.11781017.CrossRefPubMedPubMedCentral

30.

Lim CH, Hassan MRA, Tan CL, Ng BH. The effect of hydroxychloroquine on non-alcoholic fatty liver disease among rheumatoid arthritis patients. J R Coll Physicians Edinb. 2021;51(3):310–7. https://doi.org/10.4997/jrcpe.2021.322.CrossRefPubMed

31.

Faselis C, Zeng-Treitler Q, Cheng Y, et al. Cardiovascular safety of hydroxychloroquine in US veterans with rheumatoid arthritis. Arthritis Rheumatol. 2021;73(9):1589–600. https://doi.org/10.1002/art.41803.CrossRefPubMed

32.

Quiñones ME, Joseph JK, Dowell S, et al. Hydroxychloroquine and risk of long QT syndrome in rheumatoid arthritis: a veterans cohort study with 19-year follow-up. Arthritis Care Res (Hoboken). 2022. https://doi.org/10.1002/acr.25005.CrossRef

33.

Hashimoto A, Chiba N, Tsuno H, et al. Incidence of malignancy and the risk of lymphoma in Japanese patients with rheumatoid arthritis compared to the general population. J Rheumatol. 2015;42(4):564–71. https://doi.org/10.3899/jrheum.140533.CrossRefPubMed

34.

Harigai M, Nanki T, Koike R, et al. Risk for malignancy in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs compared to the general population: a nationwide cohort study in Japan. Mod Rheumatol. 2016;26(5):642–50. https://doi.org/10.3109/14397595.2016.1141740.CrossRefPubMed

35.

Nakajima A, Inoue E, Tanaka E, et al. Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA. Scand J Rheumatol. 2010;39(5):360–7. https://doi.org/10.3109/03009741003604542.CrossRefPubMed

36.

Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015;17(1):212. https://doi.org/10.1186/s13075-015-0728-9.CrossRefPubMedPubMedCentral

37.

Lee H. The risk of malignancy in Korean patients with rheumatoid arthritis. Yonsei Med J. 2019;60(2):223–9. https://doi.org/10.3349/ymj.2019.60.2.223.CrossRefPubMedPubMedCentral

38.

Simon TA, Boers M, Hochberg M, et al. Comparative risk of malignancies and infections in patients with rheumatoid arthritis initiating abatacept versus other biologics: a multi-database real-world study. Arthritis Res Ther. 2019;21(1):228. https://doi.org/10.1186/s13075-019-1992-x.CrossRefPubMedPubMedCentral

39.

Merrell MA, Ilvesaro JM, Lehtonen N, et al. Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res. 2006;4(7):437–47. https://doi.org/10.1158/1541-7786.Mcr-06-0007.CrossRefPubMed

40.

Verbaanderd C, Maes H, Schaaf MB, et al. Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience. 2017;11:781. https://doi.org/10.3332/ecancer.2017.781.CrossRefPubMedPubMedCentral

41.

Lafyatis R, York M, Marshak-Rothstein A. Antimalarial agents: closing the gate on Toll-like receptors? Arthritis Rheum. 2006;54(10):3068–70. https://doi.org/10.1002/art.22157.CrossRefPubMed

Title: Association of Hydroxychloroquine Use with a Dose-Dependent Decrease in Mortality Risk in Patients with Elderly-Onset Rheumatoid Arthritis
Authors: Ching-Tsai Lin
Wen-Nan Huang
Jun-Peng Chen
Wei-Ting Hung
Tsu-Yi Hsieh
Hsin-Hua Chen
Kuo-Tung Tang
Der-Yuan Chen
Yi-Hsing Chen
Yi-Ming Chen
Publication date: 12-05-2023
Publisher: Springer Healthcare
Keywords: Rheumatoid Arthritis
Hydroxychloroquine
Published in: Rheumatology and Therapy / Issue 4/2023
Print ISSN: 2198-6576
Electronic ISSN: 2198-6584
DOI: https://doi.org/10.1007/s40744-023-00561-1

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 4/2023

Hematologic Malignancy Risk in Inflammatory Arthritis Patients Treated with TNF Inhibitors: The Real-Life Data from the HUR-BIO Registry

Living with Systemic Sclerosis: A Patient and Physician Perspective

Pain and Inflammation as Mediators of Tofacitinib Treatment Effect on Fatigue in Patients with Ankylosing Spondylitis: A Mediation Analysis

Patient–Physician Communication and Perception of Treatment Goals in Rheumatoid Arthritis: An Online Survey of Patients and Physicians

Phase 2 Dose-Finding Study in Patients with Gout Using SEL-212, a Novel PEGylated Uricase (SEL-037) Combined with Tolerogenic Nanoparticles (SEL-110)

Benefits of Autoantibody Enrichment in Early Rheumatoid Arthritis: Analysis of Efficacy Outcomes in Four Pooled Abatacept Trials

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials